Shi Haoting, Huang Jingxuan, Wang Xue, Li Runchuan, Shen Yiqing, Jiang Bowen, Ran Jinjun, Cai Rong, Guo Fang, Wang Yufei, Ren Gang
Department of Radiation Therapy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Clinical Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Cell Dev Biol. 2023 Jul 18;11:1157841. doi: 10.3389/fcell.2023.1157841. eCollection 2023.
Reliable biomarkers are in need to predict the prognosis of hepatocellular carcinoma (HCC). Whilst recent evidence has established the critical role of copper homeostasis in tumor growth and progression, no previous studies have dealt with the copper-related genes (CRGs) signature with prognostic potential in HCC. To develop and validate a CRGs prognostic signature for HCC, we retrospectively included 353 and 142 patients as the development and validation cohort, respectively. Copper-related Prognostic Signature (Copper-PSHC) was developed using differentially expressed CRGs with prognostic value. The hazard ratio (HR) and the area under the time-dependent receiver operating characteristic curve (AUC) during 3-year follow-up were utilized to evaluate the performance. Additionally, the Copper-PSHC was combined with age, sex, and cancer stage to construct a Copper-clinical-related Prognostic Signature (Copper-CPSHC), by multivariate Cox regression. We further explored the underlying mechanism of Copper-PSHC by analyzing the somatic mutation, functional enrichment, and tumor microenvironment. Potential drugs for the high-risk group were screened. The Copper-PSHC was constructed with nine CRGs. Patients in the high-risk group demonstrated a significantly reduced overall survival (OS) (adjusted HR, 2.65 [95% CI, 1.83-3.84] and 3.30, [95% CI, 1.27-8.60] in the development and validation cohort, respectively). The Copper-PSHC achieved a 3-year AUC of 0.74 [95% CI, 0.67-0.82] and 0.71 [95% CI, 0.56-0.86] for OS in the development and validation cohort, respectively. Copper-CPSHC yield a 3-year AUC of 0.73 [95% CI, 0.66-0.80] and 0.72 [95% CI, 0.56-0.87] for OS in the development and validation cohort, respectively. Higher tumor mutation burden, downregulated metabolic processes, hypoxia status and infiltrated stroma cells were found for the high-risk group. Six small molecular drugs were screened for the treatment of the high-risk group. Copper-PSHC services as a promising tool to identify HCC with poor prognosis and to improve disease outcomes by providing potential clinical decision support in treatment.
需要可靠的生物标志物来预测肝细胞癌（HCC）的预后。虽然最近的证据已经证实铜稳态在肿瘤生长和进展中起关键作用，但之前尚无研究探讨过具有HCC预后潜力的铜相关基因（CRGs）特征。为了开发和验证一种用于HCC的CRGs预后特征，我们分别回顾性纳入了353例和142例患者作为开发队列和验证队列。使用具有预后价值的差异表达CRGs构建了铜相关预后特征（Copper-PSHC）。利用3年随访期间的风险比（HR）和时间依赖性受试者工作特征曲线下面积（AUC）来评估其性能。此外，通过多变量Cox回归将Copper-PSHC与年龄、性别和癌症分期相结合，构建了铜临床相关预后特征（Copper-CPSHC）。我们通过分析体细胞突变、功能富集和肿瘤微环境进一步探索了Copper-PSHC的潜在机制。筛选了针对高危组的潜在药物。Copper-PSHC由9个CRGs构建而成。高危组患者的总生存期（OS）显著缩短（开发队列和验证队列中调整后的HR分别为2.65 [95% CI，1.83 - 3.84]和3.30，[95% CI，1.27 - 8.60]）。Copper-PSHC在开发队列和验证队列中OS的3年AUC分别为0.74 [95% CI，0.67 - 0.82]和0.71 [95% CI，0.56 - 0.86]。Copper-CPSHC在开发队列和验证队列中OS的3年AUC分别为0.73 [95% CI，0.66 - 0.80]和0.72 [95% CI，0.56 - 0.87]。高危组具有更高的肿瘤突变负担、下调的代谢过程、缺氧状态和浸润的基质细胞。筛选出6种小分子药物用于治疗高危组。Copper-PSHC是一种很有前景的工具，可通过在治疗中提供潜在的临床决策支持来识别预后不良的HCC并改善疾病结局。
